Intermittent hypoxic-hyperoxic training improves markers of vascular aging in coronary artery disease patients – a randomized controlled trial

Background Early vascular aging (EVA) contributes to elevated cardiovascular risk and impaired hemodynamics in patients with coronary artery disease (CAD). While cardiac rehabilitation (CR) improves functional capacity, targeted therapeutic strategies to improve vascular function during CR remain limited. Intermittent hypoxic-hyperoxic training (IHHT) induces cellular adaptions that may promote vascular remodeling and improve vascular function. Purpose To investigate the effects of IHHT on markers of EVA in CAD patients undergoing CR. Methods 36 CAD patients after myocardial infarction and/or percutaneous coronary intervention referred to 3-4 weeks of inpatient CR were randomized into an IHHT (N=18; 31% female; 53.9±9.2 years) or control group (CG, N=18; 37% female; 58.4±8.0 years). Clinical assessment included pulse wave analysis (PWA), as well as cardiopulmonary exercise testing, functional tests (6-MWT and Chair-Rise Test) and disease perception questionnaires at admission and before discharge. In addition to standard CR, IHHT patients received three weekly sessions (30-40 min/session) consisting of six to eight individually adjusted cycles alternating between hypoxic (10-12% O2, 3-5 min) and hyperoxic breathing (30-35% O2). CG patients received standard care with matched breathing exercises (3 sessions/week, 30 min/session). Results Patients completed 24.8±3.6 days of CR and no adverse events were reported. IHHT patients received 6.9±1.2 sessions corresponding to 26±6 min of hypoxic breathing. Pulse Pressure Amplification (PPA) increased in IHHT but decreased in CG (+0.05±0.11 vs. −0.06±0.06; p=0.002), indicating reduced central cardiac load (decreased PPA is a key indicator of EVA). Total vascular resistance (−0.11±0.22 vs. +0.06±0.21 s/mmHg/ml; p=0.031), Augmentation Pressure (−5.27±8.88 vs. +1.38±3.86 mmHg; p=0.038) and Augmentation Index (−9.6±14.4 vs. +4.1±11.6%; p=0.004) improved significantly in IHHT compared to CG, reflecting reduced arterial stiffness and improved central hemodynamics. Peak oxygen uptake (VO₂peak) increased more in IHHT (+1.9±1.7 ml/min/kg) compared to CG (+0.8±2.3 ml/min/kg), but missed statistical significance (p=0.098). However, respiratory minute ventilation at peak exercise showed a greater improvement in IHHT (+9.3±10.6 l/min) than in CG (+2.4±9.8 l/min; p=0.049), with strong correlation between changes in ventilation and VO₂peak (r=0.83; p<0.001). Conclusion IHHT in addition to guideline-based CR significantly improves markers of EVA, particularly pulse pressure amplification and indices of arterial stiffness, suggesting favorable effects on central vascular function and cardiac afterload in CAD patients. Improvements in ventilatory efficiency and a trend toward greater VO₂peak enhancement further support potential physiological benefits of IHHT during CR.